JOURNAL OF CHEMICAL RESEARCH 2016 233
2-(2-((1H-Benzo[d]imidazol-2-yl)(2-(cyano methyl)-4-oxo-3,4-dihydro-
thieno [2,3-d] pyrimidin-5-yl) methylene)hydrazinyl)benzoic acid (11)
3049, 1672; 1H NMR: δ 6.86–6.99 (m, 4H, ArH), 7.47 (s, 1H, CH=N),
7.55–7.58 (m, 4H, ArH), 7.75 (S, 1H, thiophene), 7.89–7.91 (m, 4H,
ArH), 14.20 (s, 1H, NH, D2O exchangeable), 14.75 (s, 1H, OH, D2O
exchangeable); Anal. calcd for C27H16BrN5O3S: C, 56.85; H, 2.83; N,
12.28; found: C, 56.96; H, 2.86; N, 12.36%.
2-{4-(1H-Benzo[d]imidazol-2-yl)-7-[(4-methoxy-benzylidene)-
amino]-1-oxo-1H-thieno[3,4-d] pyridazin-2-yl}-benzoic acid (13e):
White solid (65%); m.p. 198–200 °C; IR (KBr, cm–1) ν = 3446, 3421
(OH, NH), 3032, 2974, 1672; 1H NMR: δ 3.84 (s, 3H, CH3), 7.04–8.03
(m, 14H, 12ArH + 1H thiophene + 1H, CH=N), 8.12 (s, 1H, NH, D2O
exchangeable), 11.35 (s, 1H, OH, D2O exchangeable); 13C NMR: δ
172.5, 165.2, 164.5, 163.8, 155.8, 142.2, 141.5, 139.7, 137.1, 137.8, 134.1,
130.5, 130.1, 128.0, 125.2, 124.2, 123.3, 122.8, 122.3, 120.3, 115.7,
114.2, 56.8; Anal. calcd for C28H19N5O4S: C, 64.48; H, 3.67; N, 13.43;
found: C64.59; H, 3.75; N, 13.49%.
2-{4-(1H-Benzo[d]imidazol-2-yl)-7-[(4-hydroxy-3-methoxy-
benzylidene)-amino]-1-oxo-1H-thieno[3,4-d]pyridazin-2-yl}-benzoic
acid (13f): White solid (40%); m.p. 188–190 °C; IR (KBr, cm–1) ν = 3444,
3433, 3030, 2936, 1677; 1H NMR: δ 3.54 (s, 3H, CH3), 3.78 (s, 1H, OH,
D2O exchangeable), 7.27–7.36 (m, 3H, ArH), 7.72 (s, 1H, CH=N),
7.74–7.96 (m, 4H, ArH), 7.99 (S, 1H, thiophene); 7.99–8.02 (m, 4H, ArH),
14.41 (s, 1H, NH, D2O exchangeable), 15.15 (s, 1H, OH carboxylic, D2O
exchangeable); 13C NMR: δ 172.5, 165.2, 163.8, 155.6, 149.5, 145.3, 142.2,
141.5, 139.7, 137.8, 137.1, 134.1, 130.1, 128.0, 125.2, 124.7, 124.2, 122.8,
122.5, 122.3, 120.3, 116.9, 116.3, 115.7, 56.9; Anal. calcd for C28H19N5O5S:
C, 62.56; H, 3.56; N, 13.03; found: C, 62.65; H, 3.61; N, 13.11%.
A mixture of compound 6 (4.49 g, 0.01 mol) and malononitrile (0.66
g, 0.01 mol) in 1,4-dioxane (20 mL) was treated with triethylamine
(1 mL) and heated under reflux for 4 h. The solid that formed after
cooling was filtered and crystallised from 1,4-dioxane to give
compound 11 as a white solid (72%); m.p. 194–196 °C; IR (KBr, cm–1)
1
ν = 3583, 3332, 3224, 3078, 2981, 2210, 1710, 1681; H NMR: δ 3.64
(s, 2H, CH2), 7.37 (s, 1H, thiophene), 7.51–8.27 (m, 8H, ArH), 11.10
(s, 1H, NH, D2O exchangeable), 11.32 (s, 1H, NH, D2O exchangeable),
12.43 (s, 1H, NH, D2O exchangeable), 14.44 (s, 1H, OH, D2O
exchangeable); 13C NMR: δ 172.5, 167.9, 163.3, 155.6, 148.5, 141.5,
140.5, 137.7, 134.5, 130.8, 128.1, 125.7, 125.0, 122.8, 118.3, 117.4, 115.7,
115.2, 114.9, 22.9; ESI-GCMS (m/z, 100%): 470 (M + 1+, 65); Anal.
calcd for C23H15N7O3S: C, 58.84; H, 3.22; N, 20.88; found: 58.97; H,
3.19; N, 21.04%.
2-(2-((1H-Benzo[d]imidazol-2-yl)(2-methyl-4-oxo-4H-thieno[2,3-d]
[1,3]oxazin-5-yl)methylene) hydrazinyl)benzoic acid (12)
A mixture of compound 6 (4.49 g, 0.01 mol) and acetic anhydride
(4 mL, 0.04 mol) in glacial acetic acid (10 mL) was heated under
reflux for 2 h. The solid that formed after cooling was filtered off and
crystallised from ethanol to give compound 12 as a white solid (59%);
m.p. 233–235 °C; IR (KBr, cm–1) ν = 3479, 3441, 3055, 2985, 1730,
1
1681; H NMR: δ 2.65 (s, 3H, CH3), 7.25–7.29 (m, 3H, ArH), 7.31 (s,
1H, thiophene), 7.34 (s, 2H, NH, D2O exchangeable), 7.66–7.71 (m, 2H,
ArH), 7.98–8.19 (m, 3H, ArH), 15.28 (s, 1H, OH, D2O exchangeable);
13C NMR: δ 172.5, 165.9, 162.8, 154.8, 148.5, 144.3, 141.5, 137.8, 134.5,
134.1, 131.0, 126.7, 122.8, 118.3, 117.4, 115.7, 115.2, 114.9, 18.9; ESI-
GCMS (m/z, 100%): 445 (M+, 68); Anal. calcd for C22H15N5O4S: C,
59.32; H, 3.39; N, 15.72; found: C, 59.40; H, 3.45; N, 15.81%.
2-(2-((1H-Benzo[d]imidazol-2-yl)(cyano)
methylene)hydrazinyl)
benzoic acid (14)
An ice-cold solution of sodium nitrite (6.90 g, 0.1 mol) in water
(20 mL) was added dropwise to a solution of anthranilic acid (13.71
g, 0.1 mol) in hydrochloric acid (25 mL) at 0–5 °C. After complete
addition of sodium nitrite solution, a cold solution of sodium acetate
(24.60 g, 0.3 mol) in water (100 mL) was then added to the diazonium
salt solution at 5 °C. A solution of sodium acetate (8.20 g, 0.1 mol) in
water (30 mL) was added to a stirred solution of 2-benzimidazolyl
acetonitrile (1.57 g, 0.1 mol) in a mixture of water (150 mL) and
ethanol (100 mL), and then the previously prepared diazonium salt was
added portion wise. The mixture was stirred for 2 h, allowed to stand in
the refrigerator overnight, filtered, washed with water and crystallised
from ethanol to give compound 14 as a white solid (89%); m.p. >300
°C; IR (KBr, cm–1) ν = 3357, 3062, 2206, 1690; 1H NMR: δ 7.17–7.37
(m, 3H, ArH), 7.64–7.95 (m, 2H, ArH), 7.988.02 (m, 3H, ArH), 8.14
(s, 1H, NH, D2O exchangeable), 8.16 (s, 1H, NH, D2O exchangeable),
13.78 (s, 1H, OH, D2O exchangeable); 13C NMR: δ 172.5, 155.1, 148.3,
141.5, 137.8, 134.4, 130.8, 122.8, 118.5, 117.7, 117.4, 115.7, 115.1; ESI-
GCMS (m/z, 100%): 306 (M + 1+, 89); Anal. calcd for C16H11N5O2: C,
62.95; H, 3.63; N, 22.94; found: C, 62.98; H, 3.60; N, 23.18%.
General procedure for preparation of 2-(4-(1H-Benzo[d]imidazol-
2-yl)-7-(arylidene-amino)-1-oxothieno [3,4-d]pyridazin-2(1H)-yl)
benzoic acid 13a–f
A mixture of compound 6 (4.49 g, 0.01 mol) and the respective aromatic
aldehyde (0.01 mol) in 1,4-dioxane (20 mL) was treated with piperidine
(1 mL) and heated under reflux for 4 h. The solid that formed while hot
was filtered and crystallised from benzene to afford 13a–f.
2-[4-(1H-Benzo[d]imidazol-2-yl)-7-(benzylidene-amino)-1-
oxo-1H-thieno[3,4-d] pyridazine-2-yl]benzoic acid (13a): Yellow
solid (75%); m.p. 244–246 °C; IR (KBr, cm–1) ν = 3437, 3030, 1662;
1H NMR: δ 7.23–7.29 (m, 4H, ArH), 7.36 (s, 1H, CH=N), 7.68–7.73 (m,
4H, ArH), 7.71 (S, 1H, thiophene), 7.95–8.01 (m, 5H, ArH), 14.45 (s,
1H, NH, D2O exchangeable), 15.15 (s, 1H, OH, D2O exchangeable);
Anal. calcd for C27H17N5O3S: C, 65.98; H, 3.49; N, 14.25; found: C,
66.09; H, 3.52; N, 14.33%.
2-{4-(1H-Benzo[d]imidazol-2-yl)-7-[(4-fluoro-benzylidene)-
amino]-1-oxo-1H-thieno[3,4-d] pyridazin-2-yl}-benzoic acid (13b):
Yellow solid (30%); m.p. 215–217 °C; IR (KBr, cm–1) ν = 3460,
2-(4-Amino-3-(1H-benzo[d]imidazol-2-yl)-5-cyano-6-oxopyridazin-
1(6H)-yl)benzoic acid (15)
1
3446, 3059, 1666; H NMR: δ 6.88–6.99 (m, 4H, ArH), 7.52 (s, 1H,
A mixture of compound 14 (3.05 g, 0.01 mol) and ethyl cyanoacetate
(1.13 g, 0.01 mol) in 1,4-dioxane (20 mL) was treated with
triethylamine (1 mL) and heated under reflux for 4 h. The solid product
formed upon dilution with ice-cold water containing hydrochloric
acid (2 mL) till pH 6, was collected by filtration and crystallised from
ethanol to give compound 15 as a yellow solid (70%); m.p. > 300 °C;
IR (KBr, cm–1) ν = 3305, 3059, 2222, 1678; 1H NMR: δ 3.64 (br s, 2H,
NH2, D2O exchangeable), 7.16–7.36 (m, 3H, ArH), 7.59–7.70 (m, 3H,
ArH), 7.87–8.04 (m, 2H, ArH), 12.84 (s, 1H, NH, D2O exchangeable),
15.37 (s, 1H, OH, D2O exchangeable); 13C NMR: δ 172.5, 170.9, 164.1,
155.6, 139.8, 137.8, 134.1, 130.5, 124.2, 122.8, 122.3, 120.3, 117.2,
115.7, 88.5; Anal. calcd for C19H12N6O3: C, 61.29; H, 3.25; N, 22.57;
found: C, 61.36; H, 3.28; N, 22.64%.
CH=N), 7.44–7.61 (m, 4H, ArH), 7.75–7.91 (m, 4H, ArH), 7.98 (S, 1H,
thiophene), 14.45 (s, 1H, NH, D2O exchangeable), 15.15 (s, 1H, OH,
D2O exchangeable); 13C NMR: δ 172.5, 165.2, 164.5, 163.8, 155.8,
142.2, 141.5, 139.7, 137.1, 137.8, 134.1, 130.5, 130.1, 128.0, 126.9, 126.7,
124.3, 122.8, 122.3, 120.3, 115.7, 115.2; Anal. calcd for C27H16FN5O3S:
C, 63.65; H, 3.17; N, 13.75; found: C63.76; H, 3.21; N, 13.82%.
2-{4-(1H-Benzo[d]imidazol-2-yl)-7-[(4-chloro-benzylidene)-
amino]-1-oxo-1H-thieno[3,4-d] pyridazin-2-yl}-benzoic acid (13c):
Yellow solid (45%); m.p. 190–192 °C; IR (KBr, cm–1) ν = 3446, 3419,
3057, 1670; 1H NMR: δ 7.23–7.29 (m, 4H, ArH), 7.36 (s, 1H, CH=N),
7.68–7.73 (m, 4H, ArH), 7.71 (S, 1H, thiophene), 7.95–8.01 (m, 4H,
ArH), 11.34 (s, 1H, NH, D2O exchangeable), 12.43 (s, 1H, OH, D2O
exchangeable); Anal. calcd for C27H16ClN5O3S: C, 61.66; H, 3.07; N,
13.32; found: C, 61.74; H, 3.12; N, 13.40%.
General procedure for hydrazinolysis of the cyano group of
compounds 14 and 15
2-{4-(1H-Benzo[d]imidazol-2-yl)-7-[(4-bromo-benzylidene)-
amino]-1-oxo-1H-thieno[3,4-d]pyridazin-2-yl}-benzoic acid (13d):
White solid (45%); m.p. 148–150 °C; IR (KBr, cm–1) ν = 3446, 3431,
A mixture of compound 15 (3.72 g, 0.01 mol) (for compound 16) or
compound 14 (3.05 g, 0.01 mol) (for compound 17) and 99% hydrazine